This project is part of a continuing series of controlled clinical trials evaluating the analgesic efficacy and safety of novel therapeutic agents and strategies for the control of chronic orofacial pain. Specific objectives of this project are: 1) to evaluate the analgesic potential of investigational analgesics acting through peripheral and central mechanisms; 2) to develop novel investigational strategies for optimizing evaluating therapeutic efficacy in ambulatory patients with chronic orofacial pain; and 3) to characterize the magnitude and etiology of pain and disability associated with failed temporomandibular joint implants. All clinical trials are double-blinded with random allocation of treatments to parallel groups and multiple dependent measures of analgesic efficacy, side effect liability, and neuroendocrine responses. Subjects are evaluated prior to enrollment by a multidisciplinary team to rule out possible undiagnosed medical problems, e.g. fibromyalgia, and confirm suitability based on prospective inclusion and exclusion criteria. Following participation in a study, they are provided a summary of findings and therapeutic recommendations are made to their referring physician/dentist for continued treatment. Evaluation of patients with failed TMJ implants: . Comparison of a selective COX-2 inhibitor to dual COX-1/COX-2 NSAIDs: A current protocol is evaluating the therapeutic efficacy and side effect liability of a selective inhibitor of cyclooxygenase (COX) - 2 inhibitor in comparison to a dual acting non-steroidal anti-inflammatory drug (NSAID) and a placebo. Subjects with early onset of TMD (< three months) will be initially evaluated for inclusion based on prospective inclusion/exclusion criteria and then randomly allocated to a six-week course of one of the three treatments. Daily pain diaries using standard analgesic scales will estimate analgesic efficacy; patient self-report will elicit side effects. Statistical comparison will be made between treatments with both parametric and non-parametric methods to determine if the selective COX-2 inhibitor has analgesic efficacy comparable or superior to ibuprofen for this indication. Demonstration of therapeutic equivalence or superiority to the dual COX-1/COX-2 inhibitor may provide a basis for chronic administration of COX-2 inhibitors without the potential toxicity associated with chronic NSAID administration. Evaluation of a TNF-alpha antagonist for advanced TMD: Patients with advanced stages of TMD often experience pain, limitation of opening, and diminished quality of life sufficient to force consideration of surgery or other non-validated treatments. These treatments are usually ineffective but can produce iatrogenic injury that worsens symptoms and prompts even more drastic therapies and outcomes, e.g. patients with failed TMJ implants. Recent recognition of the role of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) led to the development of two novel treatments for patients with advanced osteo- and rheumatoid arthritis. One of these drugs, etanercept (Embrel), is a soluble receptor for TNF-alpha that lowers levels of the cytokine coincident with therapeutic improvement. Subjects will be selected for this placebo-controlled clinical trial based on a history of TMD consistent with advanced stages of joint degeneration and a failure of prior therapies. Following initial evaluation, they will be randomized to six-weeks of either drug or placebo and monitored for study compliance, side effects, and the need for dose adjustments by phone. Subjects will return to the clinic at six weeks for a final assessment of clinical outcome and adverse events. Successful demonstration of therapeutic benefit for etanercept in this patient population may provide a therapeutic alternative for patients whose symptoms have persisted beyond the normal time course for remission, or who have failed other conservative treatments. The availability of a therapeutic alternative to surgery should minimize iatrogenic injury associated with failed multiple surgeries and other non-validated therapies for chronic orofacial pain. Future course of studies: The evaluation of patients with failed TMJ implants illustrates the need for prospective studies to evaluate novel and standard therapies for TMDs in order to provide patients and clinicians with objective data on efficacy and side effect liability. The need to carefully characterize subjects for these investigations, include placebo and standard treatment groups to assess assay sensitivity, and evaluate the treatments over an adequate time course provide substantial barriers to conducting such studies at one site. Efforts over the next year will be directed at developing and validating methods for conducting collaborative, multi-site clinical trials needed to objectively evaluate novel pharmacologic and non-pharmacolgic treatments or TMD and patients with failed TMJ implants. This latter group of patients is 10-15 years removed from the initial surgery and appear to be suffering from the effects of multiple failed surgeries aimed at retrieving the implant material and subsequent inflammatory response. Palliative care protocols tailored to individual patients level of disability will also be evaluated as part of this multi-site collaborative study.